This project will study the regulation of glycogen synthase kinase 3beta, its modulation by mood stabilizers and its potential role in bipolar disorder. The five-year plans to enable the candidate to develop into an independent psychiatric investigator to conduct translational research in bipolar disorder. The project provides extensive training in new research skills, including studying transcription factors and gene expression, using gene microarray techniques, and conducting clinical research. The central hypothesis for the research is that abnormal functioning of GSK3beta plays a role in the development of bipolar disorder. The hypothesis is based on the recent evidence that bipolar disorder may involve impaired neural plasticity and neural degeneration, and GSK3beta, a protein kinase with multiple regulatory functions in neuronal tissues, is a major intracellular target of the mood stabilizer lithium. Our preliminary results also indicate that three mood stabilizers have modulatory effects on GSK3beta. Three Specific Aims will be pursued to test the central hypothesis and accomplish the overall objective of this application. Specific Aim 1 will determine the role of GSK3beta in the brain-derived neurotrophic factor (BDNF)-induced cyclic AMP responsive element binding protein (CREB) transcription factor activity and its modulation by mood stabilizers. BDNF-mediated signaling and CREB will be studied because they are components of a neural-specific signaling system that appears to be impaired in mood disorders. Specific Aim 2 will determine the role of GSK3beta in BDNF-induced gene expression and its modulation by mood stabilizers. Gene expression will be studied because it is thought to be impaired in bipolar disorder and is modified by treatment with mood stabilizers. This hypothesis will be tested by measuring gene expression using gene microarray. The Specific Aims 1 and 2 provide training in studies of regulation of transcription factors and gene expression to obtain new skills in molecular biology, which is an important training component of this application. Specific Aim 3 will measure GSK3beta activity in peripheral blood lymphocytes of patients with bipolar disorder before and after treatment with lithium. This Specific Aim has a clinical research component to bridge the clinical and basic studies, and to facilitate the candidate's development of skills in translational research. The proposed research is innovative, because it will identify the role of GSK3beta in the development of bipolar disorder. The proposed research is expected to have a significant impact on understanding the pathophysiology and improving the treatment of bipolar disorder. At the completion of these studies, the candidate will have established a solid background in molecular biology techniques and clinical research enabling her to be an independent psychiatric researcher who possesses the ability to use molecular biology techniques to answer clinical questions.